Currently there is insufficient knowledge of how material properties at the nanoscale level could induce chronic toxicological injury. Addressing this knowledge gap is important for the safety assessment of engineered nanomaterials (ENMs) and the implementation of risk reduction strategies. Our long-term goal is to develop a fundamental understanding of the mechanisms by which industrially important ENMs mediate lung injury and use of this information to formulate predictive toxicological approaches that can be used for ENM safety assessment and safer design. The overall objective of this competitive renewal application is to develop a predictive paradigm for chronic pulmonary toxicity that is premised on the unique properties of rare earth oxide (REO) and fumed silica NPs towards engaging the NLRP3 inflammasome and disrupting the autophagy quality control mechanisms that regulate these inflammasomes. Our central hypothesis is that the (i) biocatalytic transformation of REOs into highly reactive REO-PO4 nanocrystals in the lysosome, and (ii) hydration- dependent reconstruction and display of highly reactive silanols on fumed silica NPs are responsible for sustained NRLP3 activation and autophagy blockade, leading to macrophage activation, epithelial- mesenchymal transition (EMT), and ultimately delayed or chronic pulmonary inflammation and fibrosis. The rationale for the proposed research is that, once it is known how unique nanoscale properties of the fumed silica and oxide NPs induce chronic lung injury, we can use this predictive paradigm for expedited safety assessment as well as safer design of these materials. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: Aim 1: To develop a predictive toxicological paradigm for chronic lung injury that is premised on rare earth oxide NP properties leading to lysosomal injury, NLRP3 inflammasome assembly and autophagy dysfunction. This scenario will be compared against acute lung injury by transition metal oxides. Aim 2: To develop a predictive toxicological paradigm that relates the framework chemistry and hydration status of fumed silica nanoparticles to a lysosome-independent mechanism of NLRP3 inflammasome activation, which originates at the surface membrane. Aim 3: To demonstrate that systematic control of the precursor chemistry and hydration conditions during flame spray pyrolysis (FSP) can be used to produce safer fumed silica NPs. Our approach is innovative, because we use a predictive toxicological paradigm that is premised on structure-activity relationships (SARS) linking cellular injury response pathways to the pathophysiology of chronic lung injury. The proposed research is significant because: (i) we will introduce a robust, quantitative scientific platform to assess ENM safety; (ii) ability to predict in vivo toxicological scenarios that reduce the need for expensive chronic exposure studies in animals; (iii) ability to speed up the rate of safety assessment and regulatory decision-making, commensurate with the number of new applications based on above material categories; (iv) development of SARs for the safer design of fumed silica NPs.